This is a five-year research plan to study the molecular and cellular events associated with (1) the growth and orientation of nerve processes, (2) the interaction between nerve and muscle cells before and shortly after their physical contact, and (3) development of the neuromuscular synapse. Specifically, we will examine the release of molecules from both the nerve and muscle cells, the response of growing neurite to a gradient of chemotropic substances, quantal and non-quantal components of transmitter release from neurons before and after nerve-muscle contact, and the role of synaptic activity in maturation of the synapse and in modulating the growth and stabilization of nerve terminals. These problems will be studied in nerve-muscle cultures prepared from the Xenopus embryos, using a combination of electrophysiological and cell biological techniques, including a newly-developed method of an excised membrane patch for assaying minute quantities of channel-inducing substances, and a whole-cell voltage-clamp method for recording synaptic currents. These studies will not only provide us new information concerning various cellular events during early phases of synaptogenesis, but are also likely to reveal some of the cellular mechanisms underlying the guidance of nerve growth, release of transmitter at the nerve terminal, and plasticity of the developing neuromuscular synapse. Our long-range goal is to understand the molecular and cellular mechanisms responsible for the development of specific neuronal connections.
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